For the past decade, lung cancer has remained, and remains the leading cause of cancer deaths. It ranks number 2 in terms of cancer incidence worldwide, after prostate and breast cancers in males and females respectively, excluding the skin. Historically, cancers of the lung were classified into two broad groups: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with the latter including adenocarcinomas and squamous and large cell carcinomas. The causal relationship of cigarette smoking and lung cancer has long been established; however, there is a growing rise of lung cancers in younger patients who never smoked, or were light smokers.
Histologically, the subsets of lung cancers can be differentiated, and managed appropriately with either surgery and/or standard chemotherapy, though with less success. However, with advances in molecular medicine and biotechnology, new cancer-driving mutations are being discovered (e.g. EGFR, ALK, PD-L1, MET), and the clinical impact of drugs targeted against these mutations are becoming increasingly evident. Thus, the National Comprehensive Cancer Network guidelines for lung cancer recommend obtaining a tissue diagnosis on highly suspicious nodules seen on CT scans. And, once the tumor is determined to be non-small cell lung cancer, the pathologist specifies the histologic type, specifically indicating whether the tumor is a squamous cell or nonsquamous carcinoma. If the tumor is deemed to be nonsquamous carcinoma of the lung, additional unstained slides are prepared and used to perform several recommended molecular tests.
Recently, among young nonsmoking, or light-smoking patients with NSCLC with high-grade features and unresponsive to aggressive therapy, a new mutation has been discovered, ROS1. The genetic sequences and 3-dimensional structure for ROS1 and ALK overlap significantly. Tumors with ROS1 rearrangement are believed to be more sensitive to crizotinib, a tyrosine kinase inhibitor, approved by the US Food and Drug Administration for the treatment of ALK mutation-positive NSCLC.
Approximately 1-2% of NSCLC harbor rearrangements of ROS1. There are approximately 1.5 million new cases annually worldwide; this accounts for about 15,000 NSCLC each year that may be positive for a ROS1 rearrangement. Many testing modalities are available to detect ROS1 rearrangements. Immunohistochemistry (IHC) has a quick turnaround time, with less labor-intensive methods. It is highly sensitive but its relatively high rate of false-positive results reduces its specificity. Thus, positive results by immunohistochemistry must be confirmed by a second method, such as fluorescence insitu hybridization (FISH). Real-time-polymerase chain reaction (PCR) and FISH assays cost more and take longer to perform than IHC testing. However, they are the most specific and sensitive tests for detecting ROS1 mutations. Screening is urgently needed to guide multiple biomarker-driven targeted therapies in patients with advanced NSCLC with rare molecular drivers.
Screening modalities recommend testing for EGFR and ALK aberrations, followed by reflex testing for ROS1, because the former are more common than ROS1 rearrangements; and ROS1 rearrangements are found in NSCLS that are EGFR/ALK-negative. EGFR, ALK and ROS1 are usually mutually exclusive. Although the alterations are uncommon, targeted therapies have been developed to treat tumors that are positive for EGFR, ALK, or ROS1 alterations, as well as other emerging targets. For tumors that are positive for EGFR sensitizing mutations, anti-EGFR therapies like erlotinib and gefitinib have demonstrated efficacy. On the other hand, inactivating EGFR mutations result in treatment resistance and are not effectively treated with erlotinib or gefitinib. Pharmaceutical agents such as osimertinib have been developed as second-line therapies for these patients. Also, mutations in ALK or ROS1 are contraindications for treatment with EGFR inhibitors.
Furthermore, ROS1 rearrangement has also been reported in glioblastoma, cholangiocarcinoma, and ovarian serous tumor of low malignant potential. This will open doors for research and development of more targeted therapy towards these tumors.
Emerging Targeted Therapies beyond ROS1
If patients are negative for EGFR, ALK, and ROS1, testing for additional genetic aberrations such as RET rearrangements, MET amplifications/gains, and MET exon 14 skipping mutations may be pursued. However, with expansion of molecular diagnostics, more laboratories are performing broad molecular profiling using techniques such as next-generation sequencing (NGS), which allows for a panel of mutations to be queried simultaneously. Identification of these uncommon aberrations has allowed for clinical trial-based studies that have demonstrated efficacy of anti-RET and anti-MET targeted therapies.